Relapse remains a major cause of failure for patients with acute leukemia undergoing hematopoietic stem cell transplantation (HSCT). Attempts to use higher doses of total body irradiation (TBI) have decreased relapse rates but have increased regimen-related toxicity resulting in little or not improvement in disease free-survival. The aim of our studies is to decrease relapse rates and improve the outcome of HSCT for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) by delivering supplemental doses of targeted to hematopoietic tissues using radiolabeled anti-CD45 antibody. In biodistribution studies, I-131-anti- CD45 antibody has delivered higher estimated radiation doses to bone marrow and spleen as compared to normal organs in 86% of patients. In this grant period, we will conduct a Phase II study of I-131-antiCD45 antibody plus CY and busulfan (BU) for patients with AML in first remission will continue. This study, which has demonstrated a low relapse rate to date, will be expanded to include two additional institutions in order to treat a total of 60 patients and to demonstrate the feasibility of exporting this approach. Should the results of this study suggest an improved outcome compared to that of conventional preparative regimens, a multicenter Phase III study comparing I-131-anti- CD45 antibody/BU/CY to BU/CY alone will be conducted. In addition, we are attempting to improve the outcome of marrow transplantation in elderly patients with advanced AML in a Phase I study combining escalating doses of I-131-anti-CD45 antibody with a non-myeloablative preparative regimen designed to establish mixed or full donor chimerism (2 Gy TBI + mycophenolate mofetil and cyclosporine followed by donor lymphocyte infusions). The ability to deliver substantial supplemental doses of radiation to marrow transplantation for acute leukemia by decreasing relapse rates without increased regimen/related toxicity.